Method for operating microchip reservoir device

ABSTRACT

A method is provided for operating a device for the containment and controlled release or exposure of a chemical substance. The method includes (i) providing a device which includes a substrate having a plurality of reservoirs, at least one chemical substance stored in the reservoirs, a plurality of metal reservoir caps, each of which closes an opening of one of said reservoir caps, and power and electrode means for disintegrating each of said reservoir caps; and (ii) disintegrating at least one of said reservoir caps, using said power and electrode means, to expose or release the chemical substance, wherein said disintegration comprises using potentiostatic or galvanostatic control to a voltage potential at said at least one reservoir cap.

CROSS-REFERENCE TO RELATED APPLICATIONS

This is a continuation of U.S. application Ser. No. 10/783,897, filedFeb. 20, 2004, now pending, which is a continuation of U.S. applicationSer. No. 09/665,303, filed Sep. 19, 2000, now U.S. Pat. No. 7,070,590,issued Jul. 4, 2006, which is a continuation-in-part of U.S. applicationSer. No. 09/022,322, filed Feb. 11, 1998, now U.S. Pat. No. 6,123,861,which is a continuation-in-part of U.S. application Ser. No. 08/675,375,filed Jul. 2, 1996, now U.S. Pat. No. 5,797,898. These applications areincorporated herein by reference in their entirety.

BACKGROUND OF THE INVENTION

This invention relates to miniaturized drug delivery devices and moreparticularly, to controlled time and rate release multi-welled drugdelivery devices.

Drug delivery is an important aspect of medical treatment. The efficacyof many drugs is directly related to the way in which they areadministered. Some therapies require that the drug be repeatedlyadministered to the patient over a long period of time. This makes theselection of a proper drug delivery method problematic. Patients oftenforget, are unwilling, or are unable to take their medication. Drugdelivery also becomes problematic when the drugs are too potent forsystemic delivery. Therefore, attempts have been made to design andfabricate a delivery device which is capable of the controlled,pulsatile or continuous release of a wide variety of moleculesincluding, but not limited to, drugs and other therapeutics.

Controlled release polymeric devices have been designed to provide drugrelease over a period of time via diffusion of the drug out of thepolymer and/or degradation of the polymer over the desired time periodfollowing administration to the patient. However, these devices arerelatively simple.

U.S. Pat. No. 5,490,962 to Cima, et al. discloses the use of threedimensional printing methods to make more complex devices which providerelease over a desired time frame, of one or more drugs. Although thegeneral procedure for making a complex device is described, specificdesigns are not detailed.

U.S. Pat. No. 4,003,379 to Ellinwood describes an implantableelectromechanically driven device that includes a flexible retractablewalled container, which receives medication from a storage area via aninlet and then dispenses the medication into the body via an outlet.U.S. Pat. Nos. 4,146,029 and 3,692,027 to Ellinwood discloseself-powered medication systems that have programmable miniaturizeddispensing means. U.S. Pat. No. 4,360,019 to Jassawalla discloses animplantable infusion device that includes an actuating means fordelivery of the drug through a catheter. The actuating means includes asolenoid driven miniature pump. All of these devices include miniaturepower-driven mechanical parts that are required to operate in the body,i.e., they must retract, dispense, or pump. These are complicated andsubject to breakdown. Moreover, due to complexity and size restrictions,they are unsuitable to deliver more than a few drugs or drug mixtures ata time.

It therefore would be desirable to provide a multi-welled deliverydevice that is relatively simple to use and manufacture, but which isdependable and capable of delivering drugs or other molecules and canoperate for weeks or years at a time. It would also be desirable toprovide such a device that provides the delivery of drugs or othermolecules in a controlled manner, such as continuously or pulsatile, andwhich operates actively or passively. It would further be desirable toprovide such a device that can hold many different drugs or othermolecules of varying dosages and is small enough to be implanted.

SUMMARY OF THE INVENTION

Devices are provided for the controlled release of molecules. Thedevices include (1) a substrate comprised of two or more substrateportions bonded together, (2) at least two reservoirs in the substratecontaining the molecules for release, and (3) a reservoir cap positionedon, or within a portion of, the reservoir and over the molecules, sothat the molecules are controllably released from the device bydiffusion through or upon disintegration of the reservoir caps. In apreferred embodiment, the substrate comprises an upper substrate portionadjacent the reservoir cap and a lower substrate portion distal thereservoir cap, such that a reservoir section in the upper substrateportion is in communication with a reservoir section in the lowersubstrate portion, the two reservoir sections forming a single reservoirwhich generally is larger than that which would be provided using thesingle substrate device.

In an alternative embodiment, an internal reservoir cap is interposedbetween a reservoir section of the upper substrate portion and areservoir section of the lower substrate portion, wherein release of themolecules from the reservoir section in the lower substrate portion iscontrolled by diffusion through or disintegration of the internalreservoir cap. The internal reservoir cap can be disintegratable so thatthe two reservoir sections thereby form a single reservoir. In thisalternative embodiment, the reservoir section of the lower substrateportion can contain molecules different in quantity, type, or bothquantity and type, from the molecules contained in the reservoir sectionof the upper substrate portion.

In a preferred embodiment, the molecule to be delivered is a drug. Thedrug can be provided alone or in a release system, such as abiodegradable matrix, or in any other pharmaceutically acceptablecarrier. Combinations of different drugs can be delivered in differentreservoirs or even in different reservoir sections as in the embodimentcontaining internal reservoir caps. The reservoirs can contain multipledrugs or other molecules in variable dosages.

Methods for making these microchip devices are also provided. Inpreferred embodiments, reservoirs are etched into two or more substrateportions using either chemical (wet) etching or plasma (dry) etchingtechniques well known in the field of microfabrication. Hundreds tothousands of reservoirs can be fabricated on a single substrate portionusing these techniques. SOI techniques also can be adapted to make thereservoirs. The reservoir sections of the substrate portions are alignedand then the portions are bonded together. The reservoirs, or portionsthereof, are filled either prior to or after the portions are bondedtogether.

Each of the reservoirs of a single microchip can contain differentmolecules and/or different amounts and concentrations, which can bereleased independently. The filled reservoirs can be capped withmaterials that passively disintegrate, materials that allow themolecules to diffuse passively out of the reservoir over time, ormaterials that disintegrate upon application of an electric potential.Release from an active device can be controlled by a preprogrammedmicroprocessor, remote control, or by biosensors.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 depicts a typical fabrication scheme for a passive deliverydevice.

FIG. 2 depicts a typical fabrication scheme for an active deliverydevice.

FIG. 3 depicts a typical device control circuitry flowsheet.

FIG. 4 depicts a passive delivery device.

FIG. 5 depicts an active delivery device.

FIG. 6 depicts an active device including insulator overlayers.

FIGS. 7 a-i are schematic views of several configurations of passivedelivery devices.

FIGS. 8 a-c are schematic views of several configurations of activedelivery devices.

FIGS. 9 a-e are cross-sectional schematic views of various embodimentsof devices having substrates formed from two fabricated substrateportions which have been joined together.

DETAILED DESCRIPTION OF THE INVENTION

Microchip devices have been provided which can accurately deliver drugsand other molecules at defined rates and times according to the needs ofthe patient or other experimental system. As used herein, a “microchip”is a miniaturized device fabricated using methods commonly applied tothe manufacture of integrated circuits and MEMS (MicroElectroMechanicalSystems) such as ultraviolet (UV) photolithography, reactive ionetching, and electron beam evaporation, as described, for example, byWolf & Tauber, Silicon Processing for the VLSI Era, Volume 1—ProcessTechnology (Lattice Press, Sunset Beach, Calif., 1986); and Jaeger,Introduction to Microelectronic Fabrication, Volume V in The ModularSeries on Solid State Devices (Addison-Wesley, Reading, Mass., 1988), aswell as MEMS methods that are not standard in making computer chips,including those described, for example, in Madou, Fundamentals ofMicrofabrication (CRC Press, 1997) and micromolding and micromachiningtechniques known in the art. The microchips provide control over therate the molecules are released as well as the time at which releasebegins. The time of release can be controlled passively or actively. Themicrochip fabrication procedure allows the manufacture of devices withprimary dimensions (length of a side if square or rectangular, ordiameter if circular) ranging from less than a millimeter to severalcentimeters. A typical device thickness is 300 μm. However, thethickness of the device can vary from approximately 10 μm to severalmillimeters, depending on the device's application. Total devicethickness and reservoir volume can also be increased by bonding orattaching additional silicon wafers or other substrate materials to thefabricated microchip device. In general, changing the device thicknessaffects the maximum number of reservoirs that may be incorporated onto amicrochip and the volume of each reservoir. In vivo applications of thedevice would typically require devices having a primary dimension of 2cm or smaller. Devices for in vivo applications are small enough to beswallowed or implanted using minimally invasive procedures. Smaller invivo devices (on the order of a millimeter) can be implanted using acatheter or other injectable means Devices for in vitro applicationshave fewer size restrictions and, if necessary, can be made much largerthan the dimension ranges for in vivo devices.

I. Device Components and Materials

Each device consists of a substrate, reservoirs, and a release systemcontaining, enclosing, or layered with the molecules to be delivered.Devices which control the release time of the molecules may includereservoir caps. Active devices may include control circuitry and a powersource.

A. The Substrate

The substrate contains the etched, molded, or machined reservoirs andserves as the support for the microchip. Any material which can serve asa support, is suitable for etching, molding, or machining, and isimpermeable to the molecules to be delivered and to the surroundingfluids, for example, water, blood, electrolytes or other solutions, maybe used as a substrate. Examples of substrate materials includeceramics, semiconductors, and degradable and non-degradable polymers.Biocompatibility of the substrate material is preferred, but notrequired. For in vivo applications, non-biocompatible materials may beencapsulated in a biocompatible material, such as poly(ethylene glycol)or polytetrafluoroethylene-like materials, before use. One example of astrong, non-degradable, easily etched substrate that is impermeable tothe molecules to be delivered and the surrounding fluids is silicon. Inanother embodiment, the substrate is made of a strong material thatdegrades or dissolves over a period of time into biocompatiblecomponents. This embodiment is preferred for in vivo applications wherethe device is implanted and physical removal of the device at a latertime is not feasible or recommended, for example, brain implants. Anexample of a class of strong, biocompatible materials are thepoly(anhydride-co-imides) discussed by K. E. Uhrich et al, “Synthesisand characterization of degradable poly(anhydride-co-imides)”,Macromolecules, 28:2184-93 (1995).

The substrate can be formed of only one material or can be a compositeor multi-laminate material, e.g., several layers of the same ordifferent substrate materials that are bonded together. Multi-portionsubstrates can include any number of layers of silicon, glasses,ceramics, semiconductors, metals, polymers, or other substratematerials. Two or more complete microchip devices also can be bondedtogether to form multi-portion substrate devices (see, e.g., FIGS. 9a-e).

B. Release System

The molecules to be delivered may be inserted into the reservoirs intheir pure form, as a liquid solution or gel, or they may beencapsulated within or by a release system. As used herein, “releasesystem” includes both the situation where the molecules are in pureform, as either a solid or liquid, or are in a matrix formed ofdegradable material or a material which releases incorporated moleculesby diffusion out of or disintegration of the matrix. The molecules canbe sometimes contained in a release system because the degradation,dissolution or diffusion properties of the release system provide amethod for controlling the release rate of the molecules. The moleculescan be homogeneously or heterogeneously distributed within the releasesystem. Selection of the release system is dependent on the desired rateof release of the molecules. Both non-degradable and degradable releasesystems can be used for delivery of molecules. Suitable release systemsinclude polymers and polymeric matrices, non-polymeric matrices, orinorganic and organic excipients and diluents such as, but not limitedto, calcium carbonate and sugar. Release systems may be natural orsynthetic, although synthetic release systems are preferred due to thebetter characterization of release profiles. The release system isselected based on the period over which release is desired, generally inthe range of at least three to twelve months for in vivo applications.In contrast, release times as short as a few seconds may be desirablefor some in vitro applications. In some cases, continuous (constant)release from a reservoir may be most useful. In other cases, a pulse(bulk) release from a reservoir may provide more effective results. Notethat a single pulse from one reservoir can be transformed into pulsatilerelease by using multiple reservoirs. It is also possible to incorporateseveral layers of a release system and other materials into a singlereservoir to achieve pulsatile delivery from a single reservoir.Continuous release can be achieved by incorporating a release systemthat degrades, dissolves, or allows diffusion of molecules through itover an extended period of time. In addition, continuous release can besimulated by releasing several pulses of molecules in quick succession.

The release system material can be selected so that molecules of variousmolecular weights are released from a reservoir by diffusion out orthrough the material or degradation of the material. Biodegradablepolymers, bioerodible hydrogels, and protein delivery systems arepreferred for release of molecules by diffusion, degradation, ordissolution. In general, these materials degrade or dissolve either byenzymatic hydrolysis or exposure to water in vivo or in vitro, or bysurface or bulk erosion. Representative synthetic, biodegradablepolymers include: poly(amides) such as poly(amino acids) andpoly(peptides); poly(esters) such as poly(lactic acid), poly(glycolicacid), poly(lactic-co-glycolic acid), and poly(caprolactone);poly(anhydrides); poly(orthoesters); poly(carbonates); and chemicalderivatives thereof (substitutions, additions of chemical groups, forexample, alkyl, alkylene, hydroxylations, oxidations, and othermodifications routinely made by those skilled in the art), copolymersand mixtures thereof. Representative synthetic, non-degradable polymersinclude: poly(ethers) such as poly(ethylene oxide), poly(ethyleneglycol), and poly(tetramethylene oxide); vinyl polymers—poly(acrylates)and poly(methacrylates) such as methyl, ethyl, other alkyl, hydroxyethylmethacrylate, acrylic and methacrylic acids, and others such aspoly(vinyl alcohol), poly(vinyl pyrolidone), and poly(vinyl acetate);poly(urethanes); cellulose and its derivatives such as alkyl,hydroxyalkyl, ethers, esters, nitrocellulose, and various celluloseacetates; poly(siloxanes); and any chemical derivatives thereof(substitutions, additions of chemical groups, for example, alkyl,alkylene, hydroxylations, oxidations, and other modifications routinelymade by those skilled in the art), copolymers and mixtures thereof.

C. Molecules to be Released

Any natural or synthetic, organic or inorganic molecule or mixturethereof can be delivered. In one embodiment, the microchip is used todeliver drugs systemically to a patient in need thereof. In anotherembodiment, the construction and placement of the microchip in a patientenables the localized release of drugs that may be too potent forsystemic delivery. As used herein, drugs are organic or inorganicmolecules, including proteins, nucleic acids, polysaccharides andsynthetic organic molecules, having a bioactive effect, for example,anaesthetics, vaccines, chemotherapeutic agents, hormones, metabolites,sugars, immunomodulators, antioxidants, ion channel regulators, andantibiotics. The drugs can be in the form of a single drug or drugmixtures and can include pharmaceutically acceptable carriers. Inanother embodiment, molecules are released in vitro in any system wherethe controlled release of a small (milligram to nanogram) amount of oneor more molecules is required, for example, in the fields of analyticchemistry or medical diagnostics. Molecules can be effective as pHbuffering agents, diagnostic agents, and reagents in complex reactionssuch as the polymerase chain reaction or other nucleic acidamplification procedures.

D. Reservoir Caps

In the passive timed release drug delivery devices, the reservoir capsare formed from a material that degrades or dissolves over time, or doesnot degrade or dissolve but is permeable to the molecules to bedelivered. These materials are preferably polymeric materials. Materialscan be selected for use as reservoir caps to give a variety ofdegradation rates or dissolution rates or permeabilities to enable therelease of molecules from different reservoirs at different times and,in some cases, different rates. To obtain different release times(amounts of release time delay), caps can be formed of differentpolymers, the same polymer with different degrees of crosslinking, or aUV polymerizable polymer. In the latter case, varying the exposure ofthis polymer to UV light results in varying degrees of crosslinking andgives the cap material different diffusion properties or degradation ordissolution rates. Another way to obtain different release times is byusing one polymer, but varying the thickness of that polymer. Thickerfilms of some polymers result in delayed release time. Any combinationof polymer, degree of crosslinking, or polymer thickness can be modifiedto obtain a specific release time or rate. In one embodiment, therelease system containing the molecules to be delivered is covered by adegradable cap material which is nearly impermeable to the molecules.The time of release of the molecules from the reservoir will be limitedby the time necessary for the cap material to degrade or dissolve. Inanother embodiment, the cap material is non-degradable and is permeableto the molecules to be delivered. The physical properties of thematerial used, its degree of crosslinking, and its thickness willdetermine the time necessary for the molecules to diffuse through thecap material. If diffusion out of the release system is limiting, thecap material delays the onset of release. If diffusion through the capmaterial is limiting, the cap material determines the release rate ofthe molecules in addition to delaying the onset of release.

II. Methods of Making the Microchip Devices

A. Fabrication of the Reservoirs

Devices are manufactured using methods known to those skilled in theart, reviewed, for example, by Wolf et at. (1986), Jaeger (1988), andMadou, Fundamentals of Microfabrication (CRC Press, 1997).

In a preferred method of microchip manufacture, depicted in FIGS. 1 and2, passive and active devices, respectively, fabrication begins bydepositing and photolithographically patterning a material, typically aninsulating or dielectric material, onto the substrate to serve as anetch mask during reservoir etching. Typical insulating materials for useas a mask include silicon nitride, silicon dioxide, and some polymers,such as polyimide. In a preferred embodiment, a thin film (approximately1000-3000 Å) of low stress, silicon-rich nitride is deposited on bothsides of a silicon wafer 30/300 in a Vertical Tube Reactor (VTR).Alternatively, a stoichiometric, polycrystalline silicon nitride (Si₃N₄)can be deposited by Low Pressure Chemical Vapor Deposition (LPCVD), oramorphous silicon nitride can be deposited by Plasma Enhanced ChemicalVapor Deposition (PECVD). Reservoirs are patterned into the siliconnitride film on one side of the wafer 32/320 by ultravioletphotolithography and either plasma etching or a chemical etch consistingof hot phosphoric acid or buffered hydrofluoric acid. The patternedsilicon nitride serves as an etch mask for the chemical etching of theexposed silicon 34/340 by a concentrated potassium hydroxide solution(approximately 20-40% KOH by weight at a temperature of 75-90° C.).Alternatively, the reservoirs can be etched into the substrate by dryetching techniques such as reactive ion etching or ion beam etching.These techniques are commonly used in the fabrication of microelectronicdevices, as reviewed, for example, by Wolf et al. (1986) and Jaeger(1988). Use of these microfabrication techniques allows theincorporation of hundreds to thousands of reservoirs on a singlemicrochip. The spacing between each reservoir depends on its particularapplication and whether the device is a passive or active device. In apassive device, the reservoirs may be less than one micron apart. In anactive device, the distance between the reservoirs may be slightlylarger (between approximately 1 and 10 μm) due to the space occupied bythe electrodes on or near each reservoir. Reservoirs can be made innearly any shape and depth, and need not pass completely through thesubstrate. In a preferred embodiment, the reservoirs are etched into a(100) oriented, silicon substrate by potassium hydroxide, in the shapeof a square pyramid having side walls sloped at 54°, and pass completelythrough the substrate (approximately 300 μm) to the silicon nitride filmon the other side of the substrate, forming a silicon nitride membrane.(Here, the silicon nitride film serves as a potassium hydroxide etchstop.) The pyramidal shape allows easy filling of the reservoirs throughthe large opening of the reservoir (approximately 500 μm by 500 μm) onthe patterned side of the substrate, release through the small openingof the reservoir (approximately 50 μm by 50 μm) on the other side of thesubstrates and provides a large cavity inside the device for storing thedrugs or other molecules to be delivered.

Multi-portion substrate devices can be formed simply by making two ormore individual substrate portions and then bonding them to one anotherwith the matching openings of the reservoir sections aligned. There aretwo main types of bonds that can be formed between substrate portions.The first are atomic-scale or molecular-scale bonds. These types ofbonds usually involve the interpenetration, intermixing, orinterdiffusion of atoms or molecules of one or more of the substrates atthe interface between the substrate materials. A preferred method ofthis type of substrate bonding for use primarily with silicon or glasssubstrates involves using heat and/or electric voltages to enable theinterdiffusion of material between the two substrates, causing amolecular-scale bond to form at the interface between silicon, glass,and other similar materials. This anodic bonding process is well knownin the art. Another embodiment of this type of bonding involves meltingand re-solidification of the top layer of one or both substrates at aninterface between two or more substrate portions. The melted materialintermixes, and upon solidification, a strong bond is formed between thesubstrate portions. In one embodiment, this melting andre-solidification can be caused by the brief application of a solvent(for example, methylene chloride) to the substrate, e.g., PLEXIGLAS™ (anacrylic) or LEXAN™ (polycarbonate). The second type of bonding methodsinvolves using a material other than the substrate material to form thebond. A preferred embodiment of this type of bonding includes the use ofchemical adhesives, epoxies, and cements. An embodiment that could beused with UV transparent substrate materials would involve UV curableepoxy. The UV curable epoxy would be spread between the two substrateportions using a method such as spin coating, the reservoirs would bealigned, and a UV light source would be used to cross-link (i.e. cure)the epoxy and bond the substrates together.

Alternatively, reservoirs also can be formed using silicon-on-insulator(SOI) techniques, such as is described in S. Renard, “Industrial MEMS onSOI,” J. Micromech. Microeng. 10:245-249 (2000). SOI methods can beusefully adapted to form reservoirs having complex reservoir shapes, forexample, as shown in FIGS. 9 b, 9 c, and 9 e. SOI wafers behaveessentially as two substrate portions that have been bonded on an atomicor molecular-scale before any reservoirs have been etched into eitherportion. SOI substrates easily allow the reservoirs (or reservoirsections) on either side of the insulator layer to be etchedindependently, enabling the reservoirs on either side of the insulatorlayer to have different shapes. The reservoir (portions) on either sideof the insulator layer then can be connected to form a single reservoirhaving a complex geometry by removing the insulator layer between thetwo reservoirs using methods such as reactive ion etching, laser,ultrasound, or wet chemical etching.

B. Fabrication of Passive Timed Release Reservoir Caps

In FIG. 1, the steps represented by 36 a, 38 a, and 40 a, are conductedusing ink jet or microinjection, while represented by 36 b, 38 b, and 40b, are conducted using spin coating. In the fabrication of passive timedrelease microchips, the reservoir cap material is injected with amicro-syringe 36 a, printed with an inkjet printer cartridge, or spincoated 36 b into a reservoir having the thin membrane of insulating maskmaterial still present over the small opening of the reservoir. Ifinjection or inkjet printing methods are used, cap formation is completeafter the material is injected or printed into the reservoir 38 a anddoes not require further processing. If spin coating is used, the capmaterial is planarized by multiple spin coatings 36 b. The surface ofthe film is then etched by a plasma, an ion beam, or chemical etchantuntil the desired cap thickness is obtained 38 b. In a preferredembodiment, the insulating material used is silicon nitride and the capmaterial is printed into the reservoir with an inkjet cartridge filledwith a solution or suspension of the cap material.

Reservoir caps control the time at which molecules are released from thereservoirs. Each reservoir cap can be of a different thickness or havedifferent physical properties to vary the time at which each releasesystem containing the molecules is exposed to the surrounding fluids.Injection, inkjet printing, and spin coating are the preferred methodsof reservoir filling and any of these methods may be used to fillreservoirs, regardless of the reservoir's shape or size. However,injection and inkjet printing are the preferred methods of filling deep(>10 μm) reservoirs or reservoirs with large openings (>100 μm). Forexample, to obtain different cap thicknesses using injection or inkjetprinting, different amounts of cap material are injected or printeddirectly into each individual reservoir. Spin coating is the preferredmethod of filling shallow (<10 μm) reservoirs, reservoirs that do notpass completely through the substrate, or reservoirs with small (<100μm) openings. Variation in cap thickness or material by spin coating canbe achieved by a repeated, step-wise process of spin coating, maskingselected reservoirs, and etching. For example, to vary cap thicknesswith spin coating, the cap material is spin coated over the entiresubstrate. Spin coating is repeated, if necessary, until the material isnearly planarized. A mask material such as photoresist is patterned tocover the cap material in all the reservoirs except one. Plasma, ionbeam, or chemical etchants are used to etch the cap material in theexposed reservoir to the desired thickness. The photoresist is thenremoved from the substrate. The process is repeated as a new layer ofphotoresist is deposited and patterned to cover the cap material in allthe reservoirs except one (the exposed reservoir is not the same onealready etched to its desired thickness). Etching of the exposed capmaterial in this reservoir continues until the desired cap thickness isobtained. This process of depositing and patterning a mask material suchas photoresist, etching, and mask removal can be repeated until eachreservoir has its own unique cap thickness. The techniques, UVphotolithography, plasma or ion beam etching, etc., are well known tothose skilled in the field of microfabrication.

Although injection, inkjet printing and spin coating are the preferredmethods of cap fabrication, it is understood that each reservoir can becapped individually by capillary action, by pulling or pushing thematerial into the reservoir using a vacuum or other pressure gradient,by melting the material into the reservoir, by centrifugation andrelated processes, by manually packing solids into the reservoir, or byany combination of these or similar reservoir filling techniques.

Once a cap fabrication method is selected, additional methods forcontrolling the time of release of molecules from a reservoir can beutilized, for example, including either UV polymerizable polymers or thelayering of release system and cap materials. In the first embodiment,where the reservoir caps are made of either an injected, inkjet printedor spin coated UV polymerizable polymer, each cap can be exposed to adifferent intensity of UV light to give varying degrees of crosslinkingand therefore, different degradation or dissolution rates for degradablecaps or different permeabilities to the molecules for non-degradablecaps. Second, layers of cap material, both degradable andnon-degradable, can be inserted between layers of the release systemcontaining the molecules to be delivered by injection, inkjet printing,spin coating, or selective crosslinking. These and other similar methodsallow complex release profiles (e.g., pulsatile delivery at irregulartime intervals) to be achieved from a single reservoir.

If desired, a passive timed release device can be fabricated withoutreservoir caps. The rate of release of the molecules is thus solelycontrolled by the physical and material properties of the release systemcontaining the molecule to be delivered.

Several possible configurations for passive delivery devices are shownin FIG. 7.

C. Fabrication of Active Timed Release Reservoir Caps

In a preferred embodiment, photoresist is patterned in the form ofelectrodes on the surface of the substrate having the reservoirs coveredby the thin membrane of insulating or dielectric material. Thephotoresist is developed such that the area directly over the coveredopening of the reservoir is left uncovered by photoresist and is in theshape of an anode. A thin film of conductive material capable ofdissolving into solution or forming soluble ions or oxidation compoundsupon the application of an electric potential is deposited over theentire surface using deposition techniques such as chemical vapordeposition, electron or ion beam evaporation, sputtering, spin coating,and other techniques known in the art. Exemplary materials includemetals such as copper, gold, silver, and zinc and some polymers, asdisclosed by Kwon et al. (1991) and Bae et al. (1994). After filmdeposition, the photoresist is stripped from the substrate. This removesthe deposited film, except in those areas not covered by photoresist(lift-off technique). This leaves conducting material on the surface ofthe substrate in the form of electrodes 360. An alternative methodinvolves depositing the conductive material over the entire surface ofthe device, patterning photoresist on top of the conductive film usingUV or infrared (IR) photolithography, so that the photoresist lies overthe reservoirs in the shape of anodes, and etching the unmaskedconductive material using plasma, ion beam, or chemical etchingtechniques. The photoresist is then stripped, leaving conductive filmanodes covering the reservoirs. Typical film thicknesses of theconductive material may range from 0.05 to several microns. The anodeserves as the reservoir cap and the placement of the cathodes on thedevice is dependent upon the device's application and method of electricpotential control.

An insulating or dielectric material such as silicon oxide (SiO_(X)) orsilicon nitride (SiN_(X)) is deposited over the entire surface of thedevice by methods such as chemical vapor deposition (CVD), electron orion beam evaporation, sputtering, or spin coating. Photoresist ispatterned on top of the dielectric to protect it from etching except onthe cathodes and the portions of the anodes directly over each reservoir380. The dielectric material can be etched by plasma, ion beam, orchemical etching techniques. The purpose of this film is to protect theelectrodes from corrosion, degradation, or dissolution in all areaswhere electrode film removal is not necessary for release.

The electrodes are positioned in such a way that when an electricpotential is applied between an anode and a cathode, the unprotected(not covered by dielectric) portion of the anode reservoir cap oxidizesto form soluble compounds or ions that dissolves into solution, exposingthe release system containing the molecules to the surrounding fluids.The molecules are released from the reservoir at a rate dependent uponthe degradation or dissolution rate of a degradable release system orthe rate of diffusion of the molecules out of or through anon-degradable release system.

Several possible configurations for active delivery devices are shown inFIG. 8.

D. Removal of the Insulator Membrane (Reservoir Etch Stop)

The thin membrane of insulating or dielectric material covering thereservoir used as a mask and an etch stop during reservoir fabricationmust be removed from the active timed release device before fillingreservoir 400 and from the passive timed release device (if thereservoir extends completely through the substrate) after fillingreservoir 44. The membrane may be removed in two ways. First, themembrane can be removed by an ion beam or reactive ion plasma. In apreferred embodiment, the silicon nitride used as the insulatingmaterial can be removed by a reactive ion plasma composed of oxygen andfluorine containing gases such as CHF₃, CF₄, or SF₆. Second, themembrane can be removed by chemical etching. For example, bufferedhydrofluoric acid (BHF or BOE) can be used to etch silicon dioxide andhot phosphoric acid can be used to etch silicon nitride.

E. Reservoir Filling

The release system containing the molecules for delivery is insertedinto the large opening of the reservoir by injection, inkjet printing orspin coating 40 a/40 b/400. Each reservoir can contain a differentmolecule and dosage. Similarly, the release kinetics of the molecule ineach reservoir can be varied by the choice of the release system and capmaterials. In addition, the mixing or layering of release system and capmaterials in each reservoir can be used to tailor the release kineticsto the needs of a particular application.

The distribution over the microchip of reservoirs filled with therelease system containing the molecules to be delivered can varydepending on the medical needs of the patient or other requirements ofthe system. For applications in drug delivery, for example, the drugs ineach of the rows can differ from each other. One row may contain ahormone and another row may contain a metabolite. Also, the releasesystem can differ within each row to release a drug at a high rate fromone reservoir and a slow rate from another reservoir. The dosages canalso vary within each row. For those devices having deep (>10 μm)reservoirs or reservoirs with large (>100 μm) openings, differences inreservoir loading can be achieved by injection or inkjet printing ofdifferent amounts of material directly into each reservoir. Variationbetween reservoirs is achieved in devices having shallow (<10 μm)reservoirs, reservoirs that do not pass completely through thesubstrate, or reservoirs with small (<100 μm) openings by a repeated,step-wise process of masking selected reservoirs, spin coating, andetching, as described above regarding the fabrication by spin coating ofpassive timed release reservoir caps. Preferably, the release system andmolecules to be delivered are mixed before application to thereservoirs. Although injection, inkjet printing and spin coating are thepreferred methods of filling reservoirs, it is understood that eachreservoir can be filled individually by capillary action, by pulling orpushing the material into the reservoir using a vacuum or other pressuregradient, by melting the material into the reservoir, by centrifugationand related processes, by manually packing solids into the reservoir, orby any combination of these or similar reservoir filling techniques.

In preferred embodiments of both active and passive release devices, thereservoir openings used for filling (i.e., the openings opposite thereservoir cap end) are sealed following reservoir filling, using any ofa variety of techniques known in the art. For example, sealing can beprovided by bonding a rigid backing plate or a thin flexible film acrossthe opening. Alternatively, the opening can be sealed by applying afluid material, e.g., an adhesive, which plugs the opening and hardensto form a seal. In another embodiment, a second substrate portion, e.g.,of a second device, can be bonded across the reservoirs openings, asshown in FIG. 9.

F. Device Packaging, Control Circuitry, and Power Source

The openings through which the reservoirs of passive and active devicesare filled are sealed by wafer bonding or with a waterproof epoxy orother appropriate material impervious to the surrounding fluids 44/440.For in vitro applications, the entire unit, except for the face of thedevice containing the reservoirs and electrodes, is encased in amaterial appropriate for the system. For in vivo applications, the unitis preferably encapsulated in a biocompatible material such aspoly(ethylene glycol) or polytetrafluoroethylene.

The mechanism for release of molecules by the active timed releasedevice does not depend on multiple parts fitted or glued together whichmust retract or dislodge. Control of the time of release of eachreservoir can be achieved by a preprogrammed microprocessor, by remotecontrol, by a signal from a biosensor, or by any combination of thesemethods, as shown schematically in FIG. 3. First, a microprocessor isused in conjunction with a source of memory such as programmable readonly memory (PROM), a timer, a demultiplexer, and a power source such asa microbattery, such as is described, for example, by Jones et al.(1995) and Bates et al. (1992). The release pattern is written directlyinto the PROM by the user. The PROM sends these instructions to themicroprocessor. When the time for release has been reached as indicatedby the timer, the microprocessor sends a signal corresponding to theaddress (location) of a particular reservoir to the demultiplexer. Thedemultiplexer sends an input, such as an electric potential, to thereservoir addressed by the microprocessor. A microbattery provides thepower to operate the PROM, timer, and microprocessor, and provides theelectric potential input that is directed to a particular reservoir bythe demultiplexer. The manufacture, size, and location of each of thesecomponents is dependent upon the requirements of a particularapplication. In a preferred embodiment, the memory, timer,microprocessor, and demultiplexer circuitry is integrated directly ontothe surface of the chip. The microbattery is attached to the other sideof the chip and is connected to the device circuitry by vias or thinwires. However, in some cases, it is possible to use separate,prefabricated, component chips for memory, timing, processing, anddemultiplexing. These are attached to the backside of the miniaturizeddelivery device with the battery. The size and type of prefabricatedchips used depends on the overall dimensions of the delivery device andthe number of reservoirs. Second, activation of a particular reservoirby the application of an electric potential can be controlled externallyby remote control. Much of the circuitry used for remote control is thesame as that used in the preprogrammed method. The main difference isthat the PROM is replaced by a signal receiver. A signal such as radiowaves, microwaves, low power laser, or ultrasound is sent to thereceiver by an external source, for example, computers or ultrasoundgenerators. The signal is sent to the microprocessor where it istranslated into a reservoir address. Power is then directed through thedemultiplexer to the reservoir having the appropriate address. Third, abiosensor is integrated into the microchip to detect molecules in thesurrounding fluids. When the concentration of the molecules reaches acertain level, the sensor sends a signal to the microprocessor toactivate one or more reservoirs. The microprocessor directs powerthrough the demultiplexer to the particular reservoir(s).

G. Electric Potential Control Methods

The reservoir caps of an active device are anodes that oxidize to formsoluble compounds and ions when a potential is applied between the anodeand a cathode. For a given electrode material and electrolyte, thereexists a range of electric potentials over which these oxidationreactions are thermodynamically and kinetically favorable. In order toreproducibly oxidize and open the reservoir caps of the device, theanode potential must be maintained within this favorable potentialrange.

There exist two primary control methods for maintaining an electrodewithin a specific potential range. The first method is calledpotentiostatic control. As the name indicates, the potential is keptconstant during reservoir activation. Control of the potential istypically accomplished by incorporating a third electrode into thesystem that has a known, constant potential, called a referenceelectrode. The reference electrode can take the form of an externalprobe whose tip is placed within one to three millimeters of the anodesurface. The potential of the anode is measured and controlled withrespect to the known potential of a reference electrode such as asaturated calomel electrode (SCE). In a preferred embodiment ofpotentiostatic control, a thin film reference electrode and potentialfeedback controller circuitry could be fabricated directly onto thesurface of the microchip. For example, a microfabricated Ag/AgClreference electrode integrated with a microchip device would enable thedevice to maintain the anode potential of an activated reservoir withinthe oxidation regime until the reservoir was completely opened. Thesecond method is called galvanostatic control. As the name indicates,the current is kept constant during reservoir activation. One drawbackto this method of control is that there is more than one stablepotential for a given current density. However, if the current densityversus potential behavior is well characterized for the microchip devicein a particular electrolyte system, the current density that willmaintain the anode in the oxidation regime will be known. In this case,the galvanostatic method of potential control would be preferable to thepotentiostatic control, because galvanostatic control does not require areference electrode.

III. Applications for the Microchip Devices

Passive and active microchip devices have numerous in vitro and in vivoapplications. The microchip can be used in vitro to deliver small,controlled amounts of chemical reagents or other molecules to solutionsor reaction mixtures at precisely controlled times and rates. Analyticalchemistry and medical diagnostics are examples of fields where themicrochip delivery device can be used. The microchip can be used in vivoas a drug delivery device. The microchips can be implanted into apatient, either by surgical techniques or by injection, or can beswallowed. The microchips provide delivery of drugs to animals orpersons who are unable to remember or be ambulatory enough to takemedication. The microchips further provide delivery of many differentdrugs at varying rates and at varying times of delivery.

In a preferred embodiment the reservoir cap enables passive timedrelease, not requiring a power source, of molecules. The reservoirs arecapped with materials that degrade or dissolve at a known rate or have aknown permeability (diffusion constant) for the molecules to bedelivered. Therefore, the degradation, dissolution or diffusioncharacteristics of the cap material determine the time at which therelease of molecules in a particular reservoir begins. In effect, themicrochip provides dual control of the release of molecules by selectionof the release system (rate controller) and selection of the capmaterial (time controller, and in some cases, rate controller).

In another preferred embodiment, the reservoir cap enables active timedrelease, requiring a power source, of molecules. In this embodiment, thereservoir caps consist of a thin film of conductive material that isdeposited over the reservoir, patterned to a desired geometry, andserves as an anode. Cathodes are also fabricated on the device withtheir size and placement dependent on the device's application andmethod of electric potential control. Conductive materials capable ofdissolving into solution or forming soluble compounds or ions upon theapplication of an electric potential, including metals such as copper,gold, silver, and zinc and some polymers, are used in the active timedrelease device. When an electric potential is applied between an anodeand cathode, the conductive material of the anode above the reservoiroxidizes to form soluble compounds or ions that dissolve into solution,exposing the release system containing the molecules to be delivered tothe surrounding fluids. Alternatively, the application of an electricpotential can be used to create changes in local pH near the anodereservoir cap to allow normally insoluble ions or oxidation products tobecome soluble. This would allow the reservoir to dissolve and exposethe release system to the surrounding fluids. In either case, themolecules to be delivered are released into the surrounding fluids bydiffusion out of or by degradation or dissolution of the release system.The frequency of release is controlled by incorporation of aminiaturized power source and microprocessor onto the microchip.Activation of any reservoir can be achieved by preprogramming themicroprocessor, by remote control, or by a signal from a biosensor.

The microchip devices and methods of fabrication thereof will be furtherunderstood by reference to the following non-limiting examples.

EXAMPLE 1 Fabrication of Active Release Microchip

-   1) Obtain double side polished, prime grade, (100) oriented silicon    wafers.    -   Wafer thickness=approximately 295-310 μm-   2) Deposit approximately 1600-1900 Å of low stress (10:1, silicon    rich) silicon nitride on both sides of the wafers in an SVG/Thermco    7000 Series vertical tube reactor (VTR).    -   Gas Flows: Ammonia (NH₃)=24 sccm        -   Dichlorosilane (SiH₂Cl₂)=253 sccm    -   Temperature=780° C.    -   Chamber Pressure=268 mtorr    -   Deposition Rate=approximately 30 Å/min.-   3) Pattern positive photoresist (PR) as squares (approximately 500    μm by 500 μm) serving as the large reservoir openings on one side of    the wafers having low stress silicon nitride deposited on them.    -   Hexamethyldisilazane deposition on both sides of the wafer        -   (“HMDS vapor prime”) in vacuum oven        -   approximately 30 min. at 150° C.    -   Photoresist (PR) Type—OCG825-20    -   PR Spin Speed and Times (for a Solitec Inc. Model 5110 spinner)        -   7 sec. at 500 rpm (coat)        -   7 sec. at 750 rpm (spread)        -   30 sec. at 3500 rpm (spin)    -   Prebake (in Blue M Model DDC-146C oven)        -   30 min. at 90° C.    -   Ultraviolet (UV) exposure for each wafer in the contact aligner        (Karl Suss Model MA4) with patterned mask        -   32 sec. at wavelength=320 nm    -   Developer Type—OCG934 1:1    -   Put exposed wafers into slightly agitated, room temperature        developer        -   Develop Time=approximately 40 seconds    -   Cascade Rinse=2 min.    -   Rinse and Dry Wafers in Spin Rinse Dryer (SRD)    -   Postbake (in Blue M Model DDC-146C oven)        -   30 min. at 120° C.-   4) Etch the VTR nitride to the underlying silicon using a plasma    etcher (Plasmaquest Series II Reactor Model 145).    -   Gas Flows: Oxygen (O₂)=2 sccm        -   Helium (He)=15 sccm        -   Carbon Tetrafluoride (CF₄)=15 sccm    -   Power: RF=10 W        -   ECR=100 W    -   Chamber Pressure=20 mtorr    -   Temperature=25° C.    -   Nitride Etch Rate=approximately 350 Å/min-   5) Remove excess PR with solvents—acetone, methanol, isopropanol.-   6) Etch the exposed silicon in aqueous potassium hydroxide (KOH) in    a wet processing hood (by Semifab, Inc.).    -   Concentration=approximately 38-40% by weight    -   Temperature=approximately 85-90° C.    -   Etch Rate=approximately 1 μm/min-   7) Post-KOH clean in a wet processing hood (by Laminaire Corp.) to    avoid K⁺ contamination in cleanroom.    -   Piranha Clean for 15 min.    -   Dump Rinse=3 times    -   Hydrofluoric Acid (HE) Dip        -   10 sec. in 50:1 water:HF solution (by volume)    -   Dump Rinse=3 times    -   Standard RCA clean    -   Rinse and Dry in SRD-   8) Pattern image reversal PR over the nitride membranes for    subsequent gold liftoff process.    -   HMDS vapor prime in vacuum oven        -   approximately 30 min. at 150° C.    -   Photoresist Type (PR)—AZ 5214 E    -   PR Spin Speed and Times (for a Solitec Inc. Model 5110 spinner)        -   6 sec. at 500 rpm (coat)        -   6 sec. at 750 rpm (spread)        -   30 sec. at 4000 rpm (spin)    -   Prebake (in Blue M Model DDC-146C oven): 30 min. at 90° C.    -   Ultraviolet (UV) exposure for each wafer in the contact aligner    -   (Karl Suss Model MA4) with patterned mask        -   40 sec. at wavelength=320 nm    -   Bake for 90 sec. on a metal plate in an oven at 120° C. (Blue M        Model DDC-146C)    -   UV flood exposure for each wafer in the contact aligner (Karl        Suss Model MA4) WITHOUT a patterned mask (expose entire wafer)        -   Approximately 200 sec. at wavelength=320 nm    -   Developer Type—AZ 422 MIF    -   Put exposed wafers into slightly agitated, room temperature        developer        -   Develop Time=approximately 1 min. 30 sec.    -   Cascade Rinse=2 min.    -   Rinse and Dry Wafers in Spin Rinse Dryer (SRD)-   9) Evaporation of gold onto the image reversal PR patterned side of    each wafer using a liftoff plate (wafer holder) in an electron beam    evaporator (Temescal Semiconductor Products Model VES 2550).    -   Gold Deposition Rate=5 Å/sec.    -   Gold Thickness=approximately 3000 Å    -   Base Pressure=approximately 5.0×10⁻⁷ torr    -   Room Temperature (no outside heating or cooling)-   10) Liftoff gold layer with acetone.-   11) Clean wafers with solvents—acetone, methanol, isopropanol.-   12) Oxygen plasma clean (ash) in a plasma etcher (Plasmaquest Series    II Reactor Model 145).    -   Gas Flows: O₂=25 sccm        -   He=15 sccm    -   Power: RF=10 W        -   ECR=200 W    -   Chamber Pressure=20 mtorr    -   Temperature=25° C.-   13) Deposit plasma-enhanced chemical vapor deposition (PECVD)    silicon dioxide over the entire surface of the wafers having the    gold electrodes on them using a PECVD chamber (Plasma-Therm 700    Series Waf'r/Batch Dual Chamber Plasma Processing System).    -   Gas Flows: 2% SiH₄ in N₂=400 sccm        -   N₂O=900 sccm    -   RF Power=20 W    -   Chamber Pressure=900 mtorr    -   Deposition Rate=approximately 250-500 Å/min.    -   Temperature 350° C.-   14) Clean wafers with solvents—acetone, methanol, isopropanol.-   15) Pattern PR to expose portions of the silicon dioxide covering    parts of the gold electrodes.    -   HMDS vapor prime in vacuum oven        -   approximately 30 min. at 150° C.    -   Photoresist (PR) Type—OCG825-20    -   PR Spin Speed and Times (for a Solitec Inc. Model 5110 spinner)        -   7 sec. at 500 rpm (coat)        -   7 sec. at 750 rpm (spread)        -   30 sec. at 3500 rpm (spin)    -   Prebake (in Blue M Model DDC-146C oven): 30 min. at 90° C.    -   Ultraviolet (UV) exposure for each wafer in the contact aligner        (Karl Suss Model MA4) with patterned mask        -   32 sec. at wavelength=320 nm    -   Developer Type—OCG934 1:1    -   Put exposed wafers into slightly agitated, room temperature        developer        -   Develop Time=approximately 55 seconds    -   Cascade Rinse=2 min.    -   Rinse and Dry Wafers in Spin Rinse Dryer (SRD)    -   Postbake (in Blue M Model DDC-146C oven): 30 min. at 120° C.-   16) Etch the exposed silicon dioxide to the gold surface with a    plasma etcher (Plasmaquest Series II Reactor Model 145).    -   Gas Flows: He=15 sccm        -   CF₄=15 sccm    -   Power: RF=10 W        -   ECR=100 W    -   Chamber Pressure=20 mtorr    -   Temperature=15° C.    -   Silicon Dioxide Etch Rate=approximately 215 Å/min.-   17) Spin photoresist on the side of the wafers having the gold    electrodes to protect the electrodes during wafer dicing.    -   Photoresist (PR) Type—OCG825-20    -   PR Spin Speed and Times (for a Solitec Inc. Model 5110 spinner)        -   7 sec. at 500 rpm (coat)        -   7 sec. at 750 rpm (spread)        -   30 sec. at 3500 rpm (spin)    -   Prebake (in Blue M Model DDC-146C oven): 30 min. at 90° C.-   18) Dice the wafers with a diesaw (Disco Automatic Dicing Saw Model    DAD-2H/6T).    -   Process yields 21 devices per 4″ wafer with each device        measuring 17 mm by 17 mm on a side-   19) Etch the nitride membrane from the back of the devices with a    plasma etcher (Plasmaquest Series II Reactor Model 145).    -   Gas Flows: O₂=2 sccm        -   He=15 sccm        -   CF₄=15 sccm    -   Power: R=10 W        -   ECR=100 W    -   Chamber Pressure=20 mtorr    -   Temperature=25° C.    -   Nitride Etch Rate=approximately 350 Å/min.-   20) Clean the devices with solvents and O₂ plasma.    -   Solvent clean—acetone, methanol, isopropanol    -   Oxygen plasma clean with a plasma etcher (Plasmaquest Series II        Reactor Model 145)        -   Gas Flows: O₂=25 sccm            -   He=15 sccm        -   Power: RF=10 W            -   ECR=200 W        -   Chamber Pressure=20 mtorr        -   Temperature=25° C.-   Fabrication of active microchip devices is complete.

EXAMPLE 2 Fabrication of Passive Release Microchip

-   1) Obtain double side polished, prime grade, (100) oriented silicon    wafers for devices having reservoirs extending completely through    the wafer or single side polished, prime grade, (100) oriented    silicon wafers for devices having reservoirs that do not extend    completely through the wafer.    -   Wafer thickness=approximately 295-310 μm for devices with        reservoirs extending completely through the wafer (devices that        do not have reservoirs extending all the way through the wafer        can be of any desired thickness)-   2) Deposit approximately 1600-1900 Å of low stress (10:1, silicon    rich) silicon nitride on both sides of the wafers in an SVG/Thermco    7000 Series vertical tube reactor (VTR).    -   Gas Flows: Ammonia (NH₃)=24 sccm        -   Dichlorosilane (SiH₂Cl₂)=253 sccm    -   Temperature=780° C.    -   Chamber Pressure=268 mtorr    -   Deposition Rate=approximately 30 Å/min.-   3) Pattern positive PR as squares (approximately 500 μm by 500 μm    for devices with reservoirs extending completely through the wafer    or any desired dimension for devices that do not have reservoirs    extending all the way through the wafer) serving as the large    reservoir openings on one side of the wafers having low stress    silicon nitride deposited on them.    -   Hexamethyldisilazane deposition on both sides of the wafer        -   (“HMDS vapor prime”) in vacuum oven        -   approximately 30 min. at 150° C.    -   Photoresist (PR) Type—OCG825-20    -   PR Spin Speed and Times (for a Solitec Inc. Model 5110 spinner)        -   7 sec. at 500 rpm (coat)        -   7 sec. at 750 rpm (spread)        -   30 sec. at 3500 rpm (spin)    -   Prebake (in Blue M Model DDC-146C oven)        -   30 min. at 90° C.    -   Ultraviolet (UV) exposure for each wafer in the contact aligner        (Karl Suss Model MA4) with patterned mask        -   32 sec. at wavelength=320 nm    -   Developer Type—OCG934 1:1    -   Put exposed wafers into slightly agitated, room temperature        developer        -   Develop Time=approximately 40 seconds    -   Cascade Rinse=2 min.    -   Rinse and Dry Wafers in Spin Rinse Dryer (SRD)    -   Postbake (in Blue M Model DDC-146C oven): 30 min. at 120° C.-   4) Etch the VTR nitride to the underlying silicon using a plasma    etcher (Plasmaquest Series II Reactor Model 145).    -   Gas Flows: Oxygen (O₂)=2 sccm        -   Helium (He)=15 sccm        -   Carbon Tetrafluoride (CF₄)=15 sccm    -   Power: RF=10 W        -   ECR=100 W    -   Chamber Pressure=20 mtorr    -   Temperature=25° C.    -   Nitride Etch Rate=approximately 350 Å/min.-   5) Remove excess PR with solvents—acetone, methanol, isopropanol.-   6) Etch the exposed silicon in aqueous potassium hydroxide (KOH) in    a wet processing hood (by Semifab, Inc.).    -   Concentration=approximately 38-40% by weight    -   Temperature=approximately 85-90° C.    -   Etch Rate=approximately 1 μm/min.-   7) Post-KOH clean in a wet processing hood (by Laminaire Corp.) to    avoid K⁺ contamination in cleanroom.    -   Piranha Clean for 15 min.    -   Dump Rinse=3 times    -   Hydrofluoric Acid (HF) Dip        -   10 sec. in 50:1 water:HF solution (by volume)    -   Dump Rinse=3 times    -   Standard RCA clean    -   Rinse and Dry in SRD        For those devices not having a nitride membrane (reservoirs not        extending completely through the wafer), fabrication of passive        microchip device is complete. Dice the wafer into individual        devices. The reservoirs of each device are ready to be filled.

Alternately, for those devices having a nitride membrane (reservoirsextend completely through the wafer), continue with the following steps.

-   8) Fill the reservoir using injection, inkjet printing, spin coating    or another method with reservoir cap materials, release system, and    molecules to be released, or any combination thereof.-   9) Seal the reservoir openings on the side of the wafer through    which the reservoirs were filled.-   10) Etch the nitride membranes on the side of the wafer opposite the    filling side by using a plasma etcher (Plasmaquest Series II Reactor    Model 145) until the cap material or release system is reached (etch    parameters may vary depending on the type of cap material or release    system under the nitride).    -   Gas Flows: Oxygen (O₂)=2 sccm        -   Helium (He)=15 sccm        -   Carbon Tetrafluoride (CF₄)=15 sccm    -   Power: RF=10 W        -   ECR=100 W    -   Chamber Pressure=20 mtorr    -   Temperature=25° C.    -   Nitride Etch Rate=approximately 350 Å/min.-   11) Spin photoresist on the side of the wafers having exposed cap    materials or release system to protect them during wafer dicing    (this step may not be necessary, depending on the type of exposed    cap material or release system).    -   Photoresist (PR) Type—OCG825-20    -   PR Spin Speed and Times (for a Solitec Inc. Model 5110 spinner)        -   7 sec. at 500 rpm (coat)        -   7 sec. at 750 rpm (spread)        -   30 sec. at 3500 rpm (spin)    -   Prebake (in Blue M Model DDC-146C oven): 30 min. at 90° C.-   12) Dice the wafers with a diesaw (Disco Automatic Dicing Saw Model    DAD-2H/6T).    -   Process yields 21 devices per 4′ wafer with each device        measuring 17 mm by 17 mm on a side-   13) Clean the devices with solvents and O₂ plasma (these steps may    not be necessary, depending on the type of exposed cap material or    release system).    -   Solvent clean—acetone, methanol, isopropanol    -   Oxygen plasma clean in a plasma etcher (Plasmaquest Series II        Reactor Model 145)        -   Gas Flows: O₂=25 sccm            -   He=15 sccm        -   Power: RF=10 W            -   ECR=200 W        -   Chamber Pressure=20 mtorr        -   Temperature=25° C.-   Fabrication of passive microchip device is complete.

EXAMPLE 3 Microchip with Passive Timed Drug Release

A passive timed release device, microchip 10 is shown in FIG. 4.Microchip 10 is formed from substrate 14. Reservoirs 16 are etched intosubstrate 14. Positioned in reservoirs 16 is a release system containingmolecules for delivery 18. The reservoirs are capped with reservoir caps12, The release system and the molecules for delivery 18 can varybetween rows 20 a, 20 b, 20 c, and within reservoirs of each row.

Microchip 10 can be inserted into solution for in vitro applications orbe implanted in a selected part of the body for in vivo applications andleft to operate without requiring further attention. When exposed to thesurrounding fluids, reservoir caps 12 will degrade or become permeableto the release system containing molecules for delivery 18.

EXAMPLE 4 Microchip with Active Controlled Time Release

A drug delivery device that provides active timed release is shown asmicrochip 100 in FIG. 5. Microchip 100 is similar to microchip 10 exceptthat microchip 100 contains electrodes that provide for active timedrelease. Microchip 100 is formed from substrate 160, release systemcontaining molecules for delivery 180, anode reservoir caps 120, andcathodes 140. Preferably, microchip 100 further includes an inputsource, a microprocessor, a timer, a demultiplexer, and a power source(not shown). The power source provides energy to drive the reactionbetween selected anodes and cathodes. Upon application of a smallpotential between the electrodes, electrons pass from the anode to thecathode through the external circuit causing the anode material tooxidize and dissolve into the surrounding fluids, exposing the releasesystem containing the molecules for delivery 180 to the surroundingfluids. The microprocessor directs power to specific electrode pairsthrough a demultiplexer as directed by a PROM, remote control, orbiosensor.

Another drug delivery device that provides active timed release is shownas microchip 200 in FIG. 6. Microchip 200, which includes substrate 260and release system containing molecules 280 for delivery, is similar tomicrochip 100, but includes different electrode configurations.Microchip 200 illustrates that the shape, size, ratio, and placement ofthe anodes and cathodes can vary.

EXAMPLE 5 Microchip Device having Multi-Portion Substrate

FIGS. 9 a-e illustrate several typical variations of the devices whereintwo or more substrate portions are attached to one another to form, forexample, a larger or composite substrate. The reservoir caps are showngenerically, that is, insulator/etch mask materials, insulator overlayermaterials, and anode/cathode materials are omitted from these Figures,except where a specific embodiment is otherwise indicated. These devicescan provide active release, passive release, or a combination thereof.

FIG. 9 a, for comparison, shows a “single” substrate device 500, whichhas substrate 510, in which reservoirs 520 are filled with molecules tobe released 540. Reservoirs 520 are covered by reservoir caps 530 andsealed with backing plate 550 or other type of seal.

FIG. 9 b shows device 600 having a substrate formed of a top substrateportion 610 a bonded to bottom substrate portion 610 b. Reservoirs 620a, in top substrate portion 610 a are in communication with reservoirs620 b in bottom substrate portion 610 b. Reservoirs 620 a/620 b arefilled with molecules to be released 640 and are covered by reservoircaps 630 and sealed with backing plate 650 or other type of seal.

FIG. 9 c shows device 700 having a substrate formed of a top substrateportion 710 a bonded to bottom substrate portion 710 b. Top substrateportion 710 a has reservoir 720 a which is in communication withreservoir 720 b in bottom substrate portion 710 b. Reservoir 720 b ismuch larger than reservoir 720 a and reservoirs 720 a/720 b containmolecules to be released 740. Reservoirs 720 a/720 b are filled withmolecules to be released 740 and are covered by reservoir cap 730 andsealed with backing plate 750 or other type of seal.

FIG. 9 d shows device 800 having a substrate formed of a top substrateportion 810 a bonded to bottom substrate portion 810 b. Top substrateportion 810 a has reservoir 820 a which contains first molecules to bereleased 840 a. Bottom substrate portion 810 b has reservoir 820 b whichcontains second molecules to be released 840 b. First molecules to bereleased 840 a can be the same or different from second molecules to bereleased 840 b. Reservoir 820 a is covered by reservoir cap 830 a andsealed by reservoir cap 830 b (formed of an anode material) andpartially by bottom substrate portion 810 b. Reservoir 820 b is coveredby internal reservoir cap 830 b and sealed with backing plate 850 orother type of seal. Cathodes 860 a and 860 b are positioned to form anelectric potential with anode reservoir cap 830 b.

In one embodiment of the device shown in FIG. 9 d, second molecules tobe released 840 b are first released from reservoir 820 b, through orfollowing the disintegration of reservoir cap 830 b, into reservoir 820a, wherein the second molecules mix with first molecules to be released840 a before the mixture of molecules is released from reservoir 820 athrough or following the disintegration of reservoir cap 830 a.

FIG. 9 e simply shows another reservoir shape configuration incross-section. Substrate portions 610 a/710 a/810 a can be formed fromthe same or different materials and can have the same or differentthicknesses as substrate portions 610 b/710 b/810 b. These substrateportions can be bonded or attached together (as described in section IIAabove) after they have been individually processed (e.g., etched), orthey may be formed before they have any reservoirs or other featuresetched or micro-machined into them (such as in SOI substrates).

Modifications and variations of the methods and devices described hereinwill be obvious to those skilled in the art from the foregoing detaileddescription. Such modifications and variations are intended to comewithin the scope of the appended claims.

1. A method of operating a device for the containment and controlledrelease or exposure of a chemical substance, the method comprising:providing a device which comprises: a substrate having a plurality ofreservoirs, at least one chemical substance stored in the reservoirs, aplurality of metal reservoir caps, each of which closes an opening ofone of said reservoirs, and power and electrode means for disintegratingeach of said reservoir caps; and disintegrating at least one of saidreservoir caps, using said power and electrode means, to expose orrelease the chemical substance, wherein said disintegration comprisesusing potentiostatic or galvanostatic control to control a voltagepotential at said at least one reservoir cap.
 2. The method of claim 1,wherein the chemical substance comprises a drug.
 3. The method of claim1, wherein the device is implanted in a patient before saiddisintegrating at least one of said reservoir caps.